Cyclodextrin (cyclodextrin, CD) is a natural cyclo-oligosaccharides product bonded by glucosidic bond of 6-15 glucose molecules after hydrolysed and bonded by the cyclodextrin gluconotransferase (CGT'ase), the common products are α-, β- and γ-CD, containing 6, 7, 8 glucose molecules respectively, presenting a circular truncated cone, with a hollow hydrophobic intracavity. The hydroxyl groups of the glucose unit are distributed outside the cavity, with hydrophilic property outside the cavity. With the special molecular structure of “hydrophobic inside and hydrophilic outside”, CD can form a super-molecule (inclusion complex) with weak reaction between host and guest molecular with a variety of small organic molecules of suitable size, to improve the physical and chemical property of the small organic molecules. Therefore, it has high research and application values for the molecular recognition, mimic enzymes and chiral separation by chromatography, etc, and the applications on the agriculture, medicine, cosmetics and food industry are more promising.
CD has a wide range of applications and research values in pharmacy, but its applications are restricted for its safety and solubility. The commonly-used β-CD, because of its small solubility small (1.85%), strong hemolysis, and strong irritation and obvious renal toxicity of non-intestinal administration of medicines, is unsuitable for non-intestinal administration, while β-CD derivatives (CDD) can overcome its shortcomings. The safety of application in pharmacy for CDD is primary consideration, which promotes the structural transformation of CD to obtain better inclusion complex or carrier materials for drugs.
CD derivative method is to realize by choosing a suitable substituent to substitute the hydroxyl group of the unmodified CD, the inclusion of the substituent destroys the hydrogen bond between the cyclodextrin molecules and changes the solid structure and the property of small inclusion molecules, thus, it changes the physiochemical properties of the water-solubility of the CD, decreases the degree of hemolysis and toxicity and improves the pharmaceutic performance. The type and amount of the substituents introduced (degree of substitution) are of great significance of the property and nature of the derivatives. A “minor” change of the type and degree of substitution generally lead to the significant change of the property and nature of the CD derivatives. A typical example is the impact of propyl group and hydroxypropyl group with C3 structure on the performance of β-CD, although the difference of the structure of substituents is one oxygen atom, however, propyl-β-CD (Pr-β-CD) can not be used for drugs, but hydroxypropyl-β-CD (HP-β-CD) has been widely used as drug excipients and used in the food industry at present due to its good water solubility, small degree of hemolysis and low toxicity. On the other hand, the change of average degree of substitution can also alter the performance and the use of derivatives, such as SBE-β-CD, the degree of hemolysis of such series of products will decrease with the increase of the degree of substitution, for instance, the degree of hemolysis of the 4-substituted derivative (SBE4-β-CD) and the single substituted derivative (SBE1-β-CD) are higher than the 7-substituted derivative, therefore, SBE7-β-CD (Degree of Substitution 6.0-7.1) can be used as drug excipients (U.S. Pat. No. 5,134,127). In addition, the change of the degree of substitution can also alter the inclusion property, for instance, the higher of the average degree of substitution of HP-β-CD, the less of complexing ability (Muller B W, Brauns U. Hydroxypropyl-B-cyclodextrin derivatives: influence of average degree of substitution on complexing ability and surface activity. J Pharm Sci, 1986, 75 (6): 571-572). The most commonly used is HP5-β-CD of the degree of substitution 5.
The structure of β-CD is characterized by two types of hydroxyl groups with total of 21 on the secondary carbon (HO-C2 and HO-C3) and primary carbon (HO-C6). During the course of derivation, the amount of the substituents and the position of substation will greatly alter, with the characteristics of rich structure isomerization. In the actual preparation, it is too difficult to obtain the derivates of single degree of substitution and the single structure. Besides the single-substituted derivatives, the polysubstituted derivatives for the practical application are the mixture of different degree of substitution at different positions, usually average degree of substitution (DS) is used to denote the degree of substitution of CD derivatives. DS refers to the average number of substituents bound with one mol of unmodified CD, for instance, SBE7-β-CD of degree of substitution of 7 means that unmodified β-CD per unit is connected by 7 sulfobutyl groups on average, but actually the compound contains multiple kinds of substituted components from the degree of 1 to 11. FP5-β-CD means the FP5-β-CD with average degree of substitution of 5, but actually containing the components of multiple degrees of substitution of hydroxypropyl group from 1 to 13.
Intermolecular hydrogen bond of β-CD is main reason for the small water solubility and renal toxicity, so the elimination of the adhesive force of the derivatives can form the groups of intermolecular hydrogen bonds. The introduction of groups due to CD derivation include two major types—hydrophobic group and hydrophilic group, which developed the following five types of derivatives: □ the introduction of hydrophobic group, alkyl-substituted CD derivatives, for instance, 2,6-dimethyl-β-CD (DM-β-CD), random methyl-β-cyclodextrin (RM-βCD) and full methylation-β-cyclodextrin, and diethyl-β-cyclodextrin. □ Hydrophilic group, hydroxyl-substituted derivatives, such as hydroxypropyl-β-CD (HP-β-CD) □ Branched-chain CD derivatives such as, glucose-group (G-β-CD), diglucose group (G-β-CD), maltose-group and di-maltose group-cyclodextrin. □ Hydrophilic carboxyl derivatives, such as carboxymethyl CD (CM-β-CD), and so on □ Ionization substituted-group, such as sulfonic-group CD-SBE4-β-CD and SBE7-β-CD, and so on.
Although the introduction of hydrophilic groups and hydrophobic groups can improve the soluable property of β-CD, the safety and irritation of the derivatives of these two types of groups are quite different. The test showed that, the sequence of degree of hemolysis of typical CDD is: β-CD>DM-β-CD>SBE1-β-CD≈HP-β-CD>SBE4-β-CD>SBE7-β-CD (1.
Rajewski, R A; Stella, V J Applications of cyclodextrins: 2. In vivo drug delivery. J. Pharm. Sci. 85 (11), 1142-1169, 1996). At present, the limited researches show that: the primary hydroxyl-substituted (60H) of β-CD normally can reduce the degree of hemolysis; and the introduction of positive ions usually can decrease the occurrence of hemolysis, and but the negative ion group has less obvious effect on reduction of the hemolytic effect; zwitterion group can normally increase the degree of hemolysis; while the positive ion groups of strong hydrophilic capacity will almost not cause hemolytic effect (M. Bost, V. Laine, F. Piland, A. Gradelle, J. Defeye, B. Perly, J. Inclusion Phenomena and Molecular Recognition in Chemistry 1997, 29, 57).
But the hemolytic tests of SBE-β-CD series of substituents showed that, with the increase of the degree of substitution of sulfobutyl group, the hemolytic performance of SBE-β-CD will significantly reduce (Rajewski, R A; Stella, V J Applications of cyclodextrins: 2. In vivo drug delivery. J. Pharm. Sci. 85 (11), 1142-1169, 1996). U.S. Pat. No. 5,134,127 reported the structure and usage of the sulfobutyl-substituted CD-ioned derivatives SBE-β-CD, the research shows that, the main advantages of SBE7-β-CD: high water solubility (>50 g/100 g H2O); strong complexing ability; no pharmacological activity, no effect on renal function; used for non-oral preparation; low GMP production costs and wide uses. The medicinal product of SBE-β-CD is SBE7-β-CD, with an average degree of substitution of from 6.0 to 7.1, average molecular weight of 2089˜2264 g/mol, which has been used for a number of drug preparation products. Another good medicinal CD derivative is hydroxypropyl-β-CD (BP-β-CD), and the degree of substitution marked in European Pharmacopoeia is within the range from 2.8 to 10.5, and the most commonly-used product is HP5-β-CD of degree of substitution of 5. The product of such substitution degree has less hemolytic property, and excellent complexing ability, thus it is widely used.
At present, most of CD derivatives are single-substituted products. In recent years, mixed substituted derivative method is developed. WO 2005042584 reports a new derivative of dual substituted sulfoalkyl-alkyl-CD (SAEx-AEy-CD). In the invention, the hydrophilic group (sulfoalkyl, SAE) and hydrophobic groups (Alkyl, AE) are introduced into CD simultaneously to realize dual poly-substituted derivation, SAEx-AEy-CD can not only improve the water-solubility, enhance the complexing ability, but also obviously reduce the hemolytic property than alkyl-CD, wherein the hemolytic role of ethyl-methyl-butyl-β-CD derivatives is equivalent to SBE4-β-CD, having good application prospect. The basic features of CD, as a drug carrier, are the complexing ability of drug molecules, and its unique function is to differentiate with other types of drug excipients. CD and its derivatives are usually much larger than the drug's molecular weight, and the CD more than the proportion of drug quality is usually used on the actual application, the practice shows that, CD derivatives of too large molecular weight will allow the ratio of excipients in the preparation too high and thus influence the function of CD, and become an important factor for restriction its application. Therefore, the derivation of CD should not only consider the water-solubility and safety, but also should control the molecular weight of the derivatives within a reasonable scope.